DESCRIPTION (Investigator's Abstract): This project is a collaborative effort between the group at Northern Kentucky University (NKU) and Dr. Edward C. Taylor of Princeton University. All of the syntheses and product purifications will be carried out at NKU. Professor Taylor's group will provide strategic advice and, for some key compounds, high resolution mass spectral analyses. Thymidylate synthase (TS, EC 2.1.1.45) is the enzyme responsible for catalyzing the de novo biosynthesis of 2'- deoxythymidine-5'-monophosphate (dTMP) from 2'- deoxyuridine-5'- monophosphate (dUMO), utilizing the coenzyme 5,10- methylenetetrahydrofolate as the source of the methyl group. Several clinically important anticancer agents, among them 5-fluorouracil and 10-progargyl-5,8-dideazafolic acid, are known to inhibit TS. The investigators propose to synthesize the N10-deaza analog of the coenzyme 5,10-methylenetetrahydrofolic acid. This compound, which lacks the crucial N-5, N-10 aminal moiety present in the coenzyme, is incapable of carrying out the essential 1-carbon transfer reactions characteristic of the TS system. Since the structure of this target molecule is close to that of the coenzyme, it is expected that the target molecule will be an inhibitor of TS and thus a potential anticancer drug. In addition, the synthesis and biological evaluation of a number of derivatives of a key intermediate aldehyde are goals of this investigation. All biological evaluations will be carried out by Dr. Gerald Grindey, Lilly Research Laboratories, Indianapolis, Indiana.